Functional impairment of monocyte-derived dendritic cells in cancer patients: involvement of p38 and ERK (p44/p42) MAPK signaling pathway

• Grant number: 12/13428-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2012
• End date: May 31, 2015
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Jose Alexandre Marzagão Barbuto
• Grantee: Bruna Zelante Barbosa
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 09/54599-5 - Dendritic cells: integrative elements of the immune system - an applied approach, AP.TEM

Abstract

Dendritic cells (DCs) are the main antigen presenting cells (APC) in the immune system due to several unique features that sets them apart from other APCs. Because of this they are extensively used in immunotherapy protocols against cancer. Despite their promising results with, this protocols haven`t achieved all their potential. One possible reason for that is that DCs and monocytes from cancer patients present differentiation and/or maturation deficits. In this context it is noteworthy to study the role of the intracellular signaling pathways ERK (p42/p44) and p38 MAPK (Mitogen-activated protein kinase), which are involved in the differentiation and maturation of monocyte-derived dendritic cells (Mo-DC), respectively. The p38MAPK pathway is activated during the cell response to stress and, considering that the tumor is a stressing microenvironment, we speculated that this pathway might be altered in cells from cancer patients. Indeed, we found a greater activation of the p38MAPK pathway in Mo-DCs from breast cancer patients during differentiation. Observations from other groups show that when the p38MAPK is early activated during differentiation, the ERK pathway is inactivated and differentiation is impaired, what can lead to the DC to become tolerogenic. Furthermore, one of the consequences of p38MAPK activation is the activation of the Heat Shock Protein 27 (HSP27), which is able to interfere with differentiation and maturation of Mo-DCs. Intriguingly, we recently observed that the mRNA of HSP27 is raised in DCs from cancer patients but the phosphorylated protein in cytoplasm is normal when compared to healthy controls. Thus this study aims to investigate the kinetics of activation of p38 and ERK MAPK during Mo-DC differentiation and the consequences of this activation in cells from breast cancer patients and healthy donors. Also, we aim to explore the possible role of HSP27 in the phenotypic and functional changes that we observe in cells from cancer patients. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

BARBOSA, Bruna Zelante. Functional commitment of monocyte derived dendritic cells from cancer patients: involvement of p38 and ERK1/2 (p44/p42) MAPK signaling pathways.. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.